18 -cell function (%, HOMA)UKPDS: Loss of b-cell function is the major determinant of disease progression in T2DMSulphonylureaAt start of UKPDS, -cell function was already compromised-cell function deteriorates over time (~4%/year)Metformin100Diet8060-cell function (%, HOMA)Disease progression in type 2 diabetesAs UKPDS demonstrated, even with intensive therapy, target glycaemic levels are not maintained long-term. One of the main reasons for this is that type 2 diabetes is a progressive disease characterised by continued, worsening -cell failure. Indeed, at the time of diagnosis, -cell function is already markedly compromised (by approximately 50%), and, as the above slide shows, function continues to worsen, even in patients receiving pharmacological treatment. Furthermore, as the extrapolation on this slide demonstrates, -cell function may have been suboptimal for 10 years prior to diagnosis.As insulin secretagogues, the efficacy of sulphonylureas may be particularly affected by continued -cell failure because of their reliance on residual -cell function.The ideal long-term treatment for diabetes should therefore address continued -cell deterioration.ReferencesUKPDS 16. Diabetes 1995;44:1249–12584020Extrapolation of -cell function prior to UKPDS–10–8–6–4–2246UKPDSYears from diagnosisAdapted from: UKPDS 16. Diabetes 1995;44:1249–1258. HOMA: homeostasis model assessment. n=4209

40 Aggressive Glycemic Control in T2DM Reduces Risk of ComplicationsRisk Reduction With 1% Decline in Updated HbA1cP <.0001P =.035P =.021P <.0001P <.000114%12%16%19%21%1537%43%30UKPDS 35: Risk Reduction in Diabetes-Related Complications(Updated HbA1c)[Note: be sure to include brief discussion linking this study with clinical data from UKPDS 33 (Lancet 1998; see p.409, 2nd column)]In the UKPDS, each 1% decrease in updated* HbA1c reduced the risk** of microvascular complications by 37%, peripheral vascular disease (PVD) by 43%, MI by 14%, stroke by 12%, heart failure by 16%, and cataract extraction by 19%, as shown on the slide. The investigators did not identify a cutoff point for HbA1c associated with the onset of risk for complications. Thus, a target value for HbA1c was not suggested, although the authors noted that HbA1c levels nearer to normal are obviously preferable.These data indicate that there is a quantitative relation between the risk of complications of diabetes and glycemia over time. The risk was shown to be lowest in patients with HbA1c concentrations <6%.*Updated = HbA1c measured over time as an updated mean of annual measurements.**As assessed by Cox regression models. Potential confounding risk factors included in all Cox models were sex, age, ethnic group, smoking (current/ever/never) at time of diagnosis of diabetes, and baseline HDL-C and LDL-C, triglyceride, presence of albuminuria ( > 50 mg/L measured in a single morning urine sample) measured after 3 months‘dietary treatment, and systolic blood pressure represented by the mean of measures at 2 and 9 months after diagnosis.Stratton IM et al. BMJ. 2000;321:45Micro-vascular diseasePVD*MIStrokeHeart failureCataract extractionDeath related to diabetesPVD = Peripheral Vascular Disease; MI = Myocardial Infarction*UKPDS 35: Prospective observational analysis of UKPDS patients (n = 4585, incidence analysis; n = 3642, relative risk analysis). Median 10.0 years of follow up.Adapted from Stratton IM, et al. BMJ. 2000;321:

44 Two Thirds of People with Type 2 Diabetes are Not at Goal1HbA1c Level% Patients<7.0%37.07.0%–8.0%25.8>8.0%37.2>9.0%20.2>10.0%12.41NHANES 1999–2000 DataT2DM represents ~90%–95% of casesAdapted from Adapted from Saydah SH, et al. JAMA. 2004;291:

45 6.2% – upper limit of normal rangeUKPDS: type 2 diabetes is progressively worsening independently on current therapies9Conventional*GlibenclamideChlorpropamideMetformin8InsulinMedian HbA1c (%)UKPDS clearly showed the need for new diabetes treatmentsIn UKPDS, the yearly median HbA1c in patients receiving conventional treatment increased steadily throughout the trial. Indeed, within 2 years of diagnosis, this group had a median HbA1c above the recommended target level of < 7.0%. In contrast, median HbA1c fell during the first year in patients receiving intensive treatment (glibenclamide, chloropropamide, metformin or insulin) but gradually increased subsequently and only remained within the recommended treatment target for the first 3–6 years of treatment (depending on assigned treatment). During the remaining years of follow-up, median HbA1c continued to rise steadily above treatment targets. This failure of existing treatments, even when used intensively in highly motivated patients highlights the need for new treatments in the management of type 2 diabetes.UKPDS methodologyUKPDS recruited 5102 patients with newly diagnosed type 2 diabetes.Conventional therapy aimed to maintain fasting plasma glucose (FPG) at < 15 mmol/l (270 mg/dl) using diet alone initially. However, sulphonylureas, insulin or metformin could be added if target FPG was not met.Patients assigned to intensive therapy had a target FPG < 6 mmol/l (108 mg/dl) and, in insulin-treated patients, a pre-meal FPG of 4–7 mmol/l (72–126 mg/dl). Non-overweight patients were randomised to insulin or sulphonylurea monotherapy initially. Overweight patients receiving intensive treatment could also be randomised to metformin. These agents could be combined if necessary to maintain target FPG during the trial.The data in this figure are from overweight patients (UKPDS 34). The HbA1c findings in non-overweight patients were similar; regardless of treatment, median HbA1c exceeded the recommended treatment targets within 8 years of therapy (UKPDS 33).ReferencesUKPDS 34. Lancet 1998;352:854–865UKPDS 33. Lancet 1998;352:837–8537Recommended treatment target ≤ 7.0†66.2% – upper limit of normal range246810Years from randomisationAdapted from: UKPDS 34. Lancet 1998:352:854–865. *Using diet initially then sulphonylureas, insulin and/or metformin if FPG > 15 mmol/l; †ADA clinical practice recommendations. n=5102

49 Historical Algorithm of Therapy for Type 2 DiabetesInadequate nonpharmacologic therapyOral agent2 Oral agents3 Oral agentsIt has been common practice to reserve insulin therapy until relatively late in the treatment plan for patients with type 2 diabetes. Typically, it is introduced after patients have failed to achieve glycaemic control with diet and with combination therapy using 2 or 3 oral hypoglycaemic agents of escalating dosages1,2Based on the time associated with various oral agent alterations (eg, titration and combination therapy), patients are often out of control for lengthy periods and thus increase the risk of complications related to chronic hyperglycaemia1Add insulinAdapted from Mudaliar S et al. In: Ellenberg and Rifkin’s Diabetes Mellitus, 6th ed. New York, NY: Appleton and Lange; 2003:1. Mudaliar S, Henry R. The oral antidiabetic agents. In: Porte D, Jr, Sherwin RS, Baron A. Ellenberg and Rifkin’s Diabetes Mellitus, 6th ed. New York, NY: Appleton and Lange; 2003:2. Riddle MC. Tactics for type II diabetes. Endocrinol Metab Clin North Am. 1997;26:

50 Possible Alternative Algorithm of Therapy for Type 2 DiabetesInadequate nonpharmacologic therapySevere symptomsSevere hyperglycaemiaKetosisPregnancyOral agent2 Oral agents3 Oral agentsClinicians may consider this proposed algorithm for the treatment of patients with type 2 diabetes. In this algorithm, insulin can be integrated into a patient’s regimen at various stages of the diseaseAdd Insulin Earlier in the Algorithm